Substituted azepino (2,1-a)isoquinoline compounds

Abstract: Compounds of the formula wherein A is are dual inhibitors of NEP and ACE. Compounds wherein A is are selective as ACE inhibitors. Methods of preparation and intermediates are also disclosed.

Description: Background Art Tricyclic lactams having a mercaptoalkanoyl sidechain and Possessing ACE and enkephalinase inhibition activity are disclosed in EP 481,522 and EP 534,363. Tricyclic lactams having a carboxyalkanoyl or carboxyalkyl sidechain and possessing ACE and enkephalinase inhibition activity are disclosed in EP 249,223, EP 492,369, EP 534,396 and EP 534,492. Fused lactam containing ACE inhibitors are disclosed in U.S. Patents 4,584,294 and 4,873,235. Summary Of The Invention This invention is directed to novel 4-substituted-5-oxo-1H-azepino[2,1-a]isoquinoline-7-carboxylic acids which possess angiotensin converting enzyme inhibition activity and some of which also possess neutral endopeptidase inhibitory activity. This invention is also directed to pharmaceutical compositions containing such selective or dual action inhibitors and the use of such compounds for manufacturing a medicament. This invention is also directed to the process for preparing such novel compounds and novel intermediates. The novel 4-substicuted-5-oxo-1H-azepino[2, 1-al]isoquinoline-7-carboxylic acids of this invention include those of the formula and pharmaceutically acceptable salts thereof wherein R 2 is hydrogen or The compounds of formula I can be prepared by coupling the acylmercapto containing sidechain of the formula with an azepino[2,1-a]isoquinoline of the formula to give the product of the formula wherein R 3 is an easily removable ester protecting group such as methyl, ethyl,t-butyl, or benzyl. The above reaction can be performed in an organic solvent such as methylene chloride and in the presence of a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicylcohexylcarbodiimide, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or carbodiimidazole. Alternatively, the acylmercapto carboxylic acid of formula II can be converted to an activated form prior to coupling such as an acid chloride, mixed anhydride, symmetrical anhydride, activated ester, etc. The product of formula IV can be converted to the mercaptan product of formula I wherein R 2 is hydrogen by methods known in the art. For example, when R 6 is methyl and R 3 is methyl or ethyl treatment with methanolic sodium hydroxide yields the products wherein R 2 is hydrogen. The products of formula I wherein R 2 is hydrogen can be acylated with an acyl halide of the formula wherein halo is F, Cl or Br or acylated with an anhydride of the formula to give other products of formula I wherein R 2 is The acylmercapto sidechain compounds of formula II are described in the literature. See, for example, Ondetti et al. U.S. Patents 4,105,776 and 4,339,600, Haslanger et al. U.S. Patent 4,801,609, Delaney et al. U.S. Patent 4,722,810, etc. The azepino[2,1-a]isoquinolines of formula III can be prepared according to the following process which also forms part of this invention. L-Hydroxynorleucine is converted to the N-protected compound of the formula wherein P 1 is an amino protecting group such as benzyloxycarbonyl or a group which together with the N-atom forms a protecting group such as phthalimido. For example, treatment with N-carbethoxyphthalimide gives the compound of formula XXI wherein P 1 -N is The compound of formula XXI is then coupled with the amino acid ester of the formula wherein R 13 is an easily removable ester protecting group such as methyl or ethyl. This coupling reaction is performed in the presence of a coupling reagent such as those listed above and yields the compound of the formula The alcohol of formula XXIII is oxidized such as by treatment with oxalyl chloride/dimethyl-sulfoxide and triethylamine to give the aldehyde of the formula The aldehyde of formula XXIV can be cyclized by treatment with a non-aqueous acid such as trifluoroacetcic acid or p-toluenesulfonic acid in a suitable solvent such as methylene chloride or chloroform to give the oxazolo[3,2-a]azepine-2,5-dione of the formula If desired, the aldehyde of formula XXIV can be treated to remove the R 13 ester protecting group prior to the cyclization reaction. The compound of formula XXV is treated under strongly acidic conditions such as trifluoromethanesulfonic acid in a suitable solvent such as methylene chloride or chloroform to give the azepino[2,1-a]-isoquinoline of the formula The compound of formula XXVI is alkylated to introduce the R 3 ester protecting group such as by treatment with diazomethane when R 3 is methyl followed by treatment to remove the P 1 protecting group. For example, when P 1 -N- is treatment with hydrazine yields the compound of formula III. The compounds of formula I contain three asymmetric centers in the benzo-fused lactam portion of the structure with an additional center possible in the side chain. While the optically pure form of the azepino[2,1-a]isoquinoline described above is preferred, all such forms are within the scope of this invention. The above described processes can utilize racemates, enantiomers, or diascereomers as starting materials. When diastereomeric compounds are prepared, they can be separated by conventional chromatographic or fractional crystallization methods. Preferably, the hydrogen attached to the bridgehead carbon is in the orientation shown below The compounds of formula I can be isolated in the form of a pharmaceutically acceptable salt. Suitable salts for this purpose are alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and salts derived from amino acids such as arginine, lysine, etc. These salts are obtained by reacting the acid form of the compound with an equivalent of base supplying the desired ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing. The compounds of formula I are dual inhibitors possessing the ability to inhibit angiotensin converting enzyme and neutral endopeptidase. Thus, all of the compounds of formula I including their pharmaceutically acceptable salts are useful in the treatment of physiological conditions in which angiotensin converting enzyme inhibitors have been shown to be useful. Such conditions include disease states characterized by abnormalities in blood pressure, intraocular pressure, and renin including cardiovascular diseases particularly hypertension and congestive heart failure, glaucoma, and renal diseases such as renal failure. The dual inhibitors are also useful in the treatment of physiological conditions in which neutral endopeptidase inhibitors have been shown to be useful. Such conditions also include cardiovascular diseases particularly hypertension, hyperaldosteronemia, renal diseases, glaucoma, as well as the relief of acute or chronic pain. Thus, the compounds of formula I are useful in reducing blood pressure and the dual inhibitors of formula I are additionally useful for this purpose due to their diuresis and natriuresis properties. The compounds of formula I including their pharmaceutically acceptable salts can be administered for these effects to a mammalian host such as man at from about 1 mg. to about 100 mg. per kg. of body weight per day, preferably from about 1 mg. to about 50 mg. per kg. of body weight per day. The compounds of formula I are preferably administered orally but parenteral routes such as subcutaneous, intramuscular, and intravenous can also be employed as can topical routes of administration. The daily dose can be administered singly or can be divided into two to four doses administered throughout the day. The inhibitors of formula I can be administered in combination with human ANF 99 - 126. Such combination would contain the inhibitor of formula I at from about 1 to about 100 mg. per kg. of body weight and the human ANF 99 - 126 at from about 0.001 to about 0.1 mg. per kg. of body weight. The inhibitors of formula I can be administered in combination with other classes of pharmaceutically active compounds. For example, a calcium channel blocker, a potassium channel activator, a cholesterol reducing agent, etc. The inhibitors of formula I or a pharmaceutically acceptable salt thereof and other pharmaceutically acceptable ingredients can be formulated for the above described pharmacetical uses. Suitable compositions for oral administration include tablets, capsules, and elixirs, and suitable compositions for parenteral administration include sterile solutions and suspensions. Suitable compositions for treating glaucoma also include topical compositions such as solutions, ointments, and solid inserts as described in U.S. Patent 4,442,089. About 10 to 500 mg. of active ingredient is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring, etc., in a unit dose form as called for by accepted pharmaceutical practice. The following examples are illustrative of the invention. Temperatures are given in degrees centigrade. Thin layer chromatography (TLC) was performed in silica gel unless otherwise stated. Example 1 [4S-[4α(R*),7α,12bα]]-1,2,3,4,5,7,8,12-b-Octahydro-4-[(2-mercanto-1-oxo-3-phenylpropyl)amino]-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid a) (S)-2-Phthalimido-6-hydroxyhexanoic acid A solution of (+)-L-ε-hydroxynorleucine [prepared according to the procedure of Bodanszky et al., J. Med Chem., 1978, 21 , 1030 - 1035] (1.030 g., 7.0 mmol.) and sodium carbonate (745 mg., 7.0 mmol.) in water (12 mL) was treated with N-carbethoxyphthalimide (1.495 g., 7.0 mmol.) and the mixture was stirred at room temperature for 2 hours. The solution was filtered, cooled to 0°C., and acidified with 6N hydrochloric acid to afford a white precipitate. The solid was collected by filtration and dried in vacuo at 80°C. for 1 hour to give 1.297 g. of the title compound; m.p. 162 - 163°C.; [α] D = -35.7° (c = 1.3, methanol). b) (R*)-N-(2-Phthalimido-6-hydroxy-1-oxohexyl)-L-phenylalanine, ethyl ester To a solution of L-phenylalanine ethyl ester hydrochloride salt (998 mg., 4.3 mmol) in dimethylformamide (10 mL.) was added with 4-methylmorpholine (575 µl, 529 mg., 5.2 mmol.) After stirring at room temperature for 5 minutes, the solution was cooled to 0°C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0°C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5 N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (1:1 - acetone:hexanes) R f = 0.30. c) (R*)-N-(2-Phthalimido-1,6-dioxohexyl)-L-phenylalanine, ethyl ester A -78°C. solution of oxalyl chloride (370 µL, 538 mg., 4.2 mmol.) in methylene chloride (10 mL) was treated dropwise with a solution of dry dimethylsulfoxide (610 µL, 672 mg., 8.6 mmol.) in methylene chloride (1.5 mL). After 10 minutes, a solution of the product from part (b) (1.616 g., 3.6 mmol.) in methylene chloride (10 mL) was added. After an additional 15 minutes, the mixture was treated with triethylamine (4.0 mL), stirred at -78°C. for 5 minutes, then let warm to 0°C. The resulting white slurry was partitioned between 0.5 N hydrochloric acid and ethyl acetate. The organic extract was washed with brine, then dried (sodium sulfate), filtered and stripped. The residue was flash chromatographed (Merck silica gel, 40:60-acetone: hexanes) to afford 1.474 g. of title product as an oil/foam. TLC (1:1 - acetone:hexanes) R f = 0.45. d) [3S-(3α,6β,9aα)]-Tetrahydro-3-(phenylmethyl)-6-phthalimido-oxazolo[3,2-a]azepine-2,5(3H,6H)-dione A mixture of the product from part (c) (6.11 g., 13.6 mmol.) and trifluoroacetic acid (34 mL) in chloroform (205 mL) was refluxed for 6 days. The solution was cooled to room temperature and neutralized with saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with methylene chloride. The pooled organic layers were washed with water, dried (sodium sulfate), filtered and stripped to give a dark yellow-orange oil. The residue was flash chromatographed (Merck silica gel, 40 to 60% ethyl acetate in hexanes) to afford 3.075 g. of the title product as a white foam (92:8 mixture of C-7 diastereomers as determined by NMR). TLC (1:1 - ethyl acetate:hexanes) R f = 0.37. e) [4S-(4α,7α,12bα)]-1,2,3,4,5,7,8,12b-Octahydro-4-phthalimido-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid, methyl ester To a slightly chilled (10 °C.) solution of trifluoromethanesulfonic acid (20 g) and trifluoromethanesulfonic anhydride (3.0 mL) was added a solution of the product from part (d) (1.50 g., 3.70 mmol) in methylene chloride (50 mL), resulting in a pale-yellow, non-homogeneous mixture. After stirring at room temperature for 21 hours, the solution was poured onto crushed ice and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried (sodium sulfate), filtered and stripped to give a foam. The foam was dissoved in methanol and methylene chloride and treated with excess ethereal diazomethane for 5 minutes. The excess diazomethane was destroyed by the addition of acetic acid and the solvent was removed on the rotary evaporator to give a solid. The residue was recrystallized from methylene chloride/ethyl acetate/ethyl ether to afford 880 mg. of pure title product. The mother liquor was flash chromatographed (Merck silica gel, 1:1 - ethyl acetate:hexanes) and the desired fractions were stripped and the residue crystallized as above to give an additional 236 mg. of product for a total yield of 1.116 g., m.p. 254 - 256°C. TLC (1:1 - ethyl acetate:hexanes) R f = 0.25; [α] D = -204.7° (c = 0.5, chloroform). f) [4S-(4α,7α,12bα)]-1,2,3,4,5,7,8,12b-Octahydro-4-amino-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid, methyl ester A solution of the product from part (e) (720 mg., 1.72 mmol.) in methanol (6 mL) was treated with hydrazine monohydrate (184 µL, 190 mg., 3.80 mmol.). After stirring at room temperature for 17 hours, the mixture, now thick with precipitate, was cooled to 0°C and stirred with 10 mL 1 N hydrochloric acid for 2 hours. The solution was filtered and the filtrate was washed with ethyl acetate. The ethyl acetate layer was extracted once with 0.5 N hydrochloric acid and the pooled aqueous layers were made basic with 1 N sodium hydroxide (approximately 13 mL). The aqueous mixture was extracted three times with methylene chloride and the pooled methylene chloride extracts were dried (sodium sulfate), filtered and stripped to give 514 mg. of essentially pure title product as a white oil/foam. TLC (8:1:1 - methylene chloride:acetic acid:methanol) R f = 0.50. g) (S)-2-(Acetylthio)benzenepropanoic acid Sodium nitrite (10.3 g., 280 mmol.) was added to a solution of D-phenylalanine (30.0 g., 181 mmol.) and potassium bromide (73.5 g.) in sulfuric acid (2.5 N, 365 ml.) over a period of one hour while maintaining the temperature of the reaction mixture at 0°C. The mixture was stirred for an additional hour at 0°C and then for one hour at room temperature. The reaction solution was extracted with ether, the ether was back extracted with water, and the ether layer was dried over sodium sulfate. Ether was removed in vacuo , and distillation of the oily residue afforded 25.7 g. of (R)-2-bromo-3-benzenepropanoic acid; b.p. 141° (0.55 mm of Hg.); [α] D = +14.5° (c = 2.4, chloroform). A mixture of thioacetic acid (7 ml., 97.9 mmol.) and potassium hydroxide (5.48 g., 97.9 mmol.) in acetonitrile (180.5 ml.) was stirred under argon at room temperature for 1 3/4 hours. The mixture was cooled in an ice-bath, and a solution of (R)-2-bromo-3-benzenepropanoic acid (20.4 g., 89 mmol.) in acetonitrile (20 ml.) was added over a ten minute period. The reaction was stirred under argon at room temperature for 5 hours, filtered, and the acetonitrile was removed in vacuo . The oily residue was redissolved in ethyl acetate and washed with 10% potassium bisulfate and water. Removal of the ethyl acetate in vacuo afforded 19.6 g. of crude product. The crude product was purified via its dicyclohexylamine salt using isopropyl ether as solvent for crystallization. An analytical sample of (S)-2-(acetylthio)benzenepropanoic acid, dicyclohexylamine salt was prepared by recrystallization from ethyl acetate; m.p. 146-147°; [α] D = -39.6° (c = 1.39, chloroform). Anal. calc'd. for C 11 H 12 O 3 S · C 12 H 23 N: C,68.11; H,8.70; N,3.45; S,7.91 Found: C,67.93; H,8.71; N,3.37; S,7.94. The free acid was regenerated by suspending the dicyclohexylamine salt in water, acidifying with 1 N hydrochloric acid and extracting with ethyl acetate to yield (S)-2-(acetylthio)benzenepropanoic acid; [α] D = -70.1° (c = 1.91, chloroform). Anal. calc'd. for C 11 H 12 O 3 S: C,58.91; H,5.39; S,14.30 Found: C,58.73; H,5.41; S,14.53. h) [4S-[4α(R*),7α,12bα]]-1,2,3,4,5,7,8,12b-Octahydro-4-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid, methyl ester A cold (0°C.) solution of the product from part (f) (1.72 mmol.) and (S)-2-(acetylthio)benzene-propanoic acid (445 mg., 1.99 mmol.) in methylene chloride (15 mL) was treated with triechylamine (275 µL, 200 mg, 1.98 mmol) followed by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (838 mg., 1.89 mmol.). The solution was stirred at 0°C for one hour and then at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and 0.5 N hydrochloric acid and washed successively with water and saturated sodium bicarbonate/brine. The solution was dried (sodium sulfate), filtered and stripped. The residue was flash chromatographed (Merck silica gel, 40% to 60% acetone in hexanes) to give 766 mg. of pure title product as a white foam. TLC (1:1 - acetone: hexanes) R f = 0.39. i) [4S-[4α(R*),7α,12bα]]-1,2,3,4,5,7,8,12b-Oxahydro-4-[(2-mercanto-1-oxo-3-phenylpropyl)-aminol-5-oxo-azenino[2,1-a]isoquinoline-7-carboxylic acid A cold (0 °C) solution of the product from part (h) (652 mg., 1.32 mmol.) in methanol (10 mL, deoxygenated via argon bubbling) was treated with 1 N sodium hydroxide (10 mL, deoxygenated via argon bubbling). After stirring for 1 hour, the solution was warmed to room temperature, treated with 5 mL of tetrahydrofuran and stirring was continued for an additional 2 hours. The mixture was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, then dried (sodium sulfate), filtered and stripped to afford an oil. The material was flash chromatographed (Merck silica gel, ethyl acetate followed by 2% acetic acid in ethyl acetate). The desired fractions were pooled, stripped, and azeotroped twice with ethyl acetate. The mixture was dissolved in a small amount of methylene chloride and triturated with hexane to give a foam. The volatiles were stripped, the residue was slurried in hexane, stripped to dryness again, and air dried to give 430 mg. of the title product as a relatively hard white foam. TLC (5% acetic acid in ethyl acetate) R f = 0.05; [α] D = -38.7° (c = 0.64, chloroform). HPLC: YMC S3 ODS column (6.0 x 150 mm); eluted with 40% A: 90% water-10% methanol-0.2% phosphoric acid and 60% B: 10% water-90% methanol-0.2% phosphoric acid; flow rate 1.5 mL/min detecting at 220 nm; t R = 18.72 min. (100%). Anal. calc'd. for C 24 H 26 N 2 O 4 S · 0.32 H 2 O: C, 64.88; H, 6.04; N, 6.30; S. 7.22 Found: C, 64.88; H. 6.41; N, 5.87; S, 7.09. EXAMPLE 2 1000 tablets each containing the following ingredients: [4S-[4α(R*),7α,12bα]]-1,2,3,4, 5,7,8,12b-Octahydro-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid 200 mg. Cornstarch 100 mg. Gelatin 20 mg. Avicel(microcrystalline cellulose) 50 mg. Magnesium stearate 5 mg. 375 mg. are prepared from sufficient bulk quantities by mixing the product of Example 1 and cornstarch with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation. The mixture is then compressed in a tablet press to form 1000 tablets each containing 200 mg. of active ingredient. Similar procedures can be employed to form tablets or capsules containing from 50 mg. to 500 mg. of active ingredient.

Claims: A compound of the formula or a pharmaceutically acceptable salt thereof wherein: R 2 is hydrogen or The compound of Claim 1, [4S-[4α(R*),-7α, 12bα]]-1, 2, 3, 4, 5, 7, 8, 12b-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl]amino]-5-oxo-azepino[2,1-a]isoquinoline-7-carboxylic acid. A pharmaceutical composition useful in the treatment of cardiovascular disease such as hypertension and congestive heart failure comprising a pharmaceutically acceptable carrier and one or more compounds according to claim 1. A compound of claim 1 for use as a therapeutic agent. Use of a compound of claim 1 for manufacturing a medicament for inhibiting angiotensin converting enzyme. Use of a compound of claim 1 for manufacturing a medicament for inhibiting neutral endopeptidase. Use of a compound of Claim 1 for manufacturing a medicament for treating hypertension, congestive heart failure, glaucoma, renal diseases, hyperaldosteronemia or acute or chronic pain. A process for preparing a compound of the formula which comprises coupling the acylmercapto sidechain of the formula or an activated form thereof with the amine of the formula wherein R 6 is straight or branched chain alkyl of 1 to 4 carbon atoms or phenyl and R 3 is straight or branched chain alkyl of 1 to 4 carbon atoms or benzyl followed by removal of the acyl group and the R 3 ester protecting group. A compound of the formula wherein R 3 is hydrogen, straight or branched chain alkyl of 1 to 4 carbons, or benzyl. The compound of claim 9 wherein R 3 is methyl. A process for preparing compounds of the formula wherein R 3 is straight or branched chain alkyl of 1 to 4 carbon atoms or benzyl which comprises: a) coupling an amino acid of the formula wherein P 1 is an amino protecting group or taken together with the N-atom completes an amino protecting group, with the amino acid ester of the formula to give the dipeptide wherein R 13 is an easily removable ester protecting group; b) converting the product from part (a) to the aldehyde c) cyclizing the product from part (b) by treatment with acid to give d) treating the oxazole[3,2-a]azepine-2,5-dione product from part (c) under strongly acidic conditions to give and e) treating the azepino[2,1-a]isoquinoline product from part (d) to introduce the R 3 ester group and remove the N-protecting group.

Inventors: ROBL JEFFREY A, ROBL, JEFFREY A.
Applicants: SQUIBB BRISTOL MYERS CO, BRISTOL-MYERS SQUIBB COMPANY
Application year: 1994
Main classification: C07K5
IPC codes: A61P9, A61K31, A61P43, C07K5, C07D471, C07F9